Antibody responses to classical T cell-independent (TI) antigens such as bacterial capsular polysaccharides are highly protective, and play a critical role in controlling a number of clinically important infections. For reasons that remain poorly understood young children cannot mount antibody responses to TI antigens and as a consequence are much more prone to suffer from life-threatening infections, particularly from encapsulated bacterial pathogens. As with young children, young mice respond poorly to polysaccharide antigens, while human adults as well as adult mice can mount a very efficient response to polysaccharide antigens. B1b lymphocytes are a subset of mature B cells that increases in number in response to a variety of TI antigens including type 3 polysaccharide of Streptococcus pneumoniae (PPS3), 1,3 dextran of Enterobacter cloacae, Vi polysaccharide of Salmonella typhi and Factor H binding protein A, a surface antigen of Borrelia hermsii. Furthermore, these cells generate rapid primary antibody as well as long-lasting memory B cell responses. Despite having B1b cells, young mice are impaired in responding to polysaccharide antigens, suggesting that B cells in the young are distinct from those in adults. Since B lymphopoeisis early in life is largely IL-7- independent, while in adults it is IL-7-dependent, we hypothesize that B cells developed in the presence of IL-7 are required for generating anti-polysaccharide antibody responses. In support of this, we found that despite having B1b cells, young wildtype, adult IL-7-/- or adult IL-7R-/- mice are severely impaired in responding to classical TI antigens such as 4-hydroxy-3-nitrophenyl-acetyl-Ficoll (NP-Ficoll), bacterial dextran and PPS vaccine, and do not survive S. pneumoniae challenge after PPS immunization. Furthermore, we found that transgenic expression of IL-7 promotes the anti-PPS response in young and confers protective immunity to S. pneumoniae. These data support the hypothesis that IL-7-dependent B cells play a crucial role in generating TI humoral immunity. To translate these findings to human infants we have utilized neonatal NOD/SCID/cnull mice engrafted with human umbilical cord blood CD34+ hematopoietic stem cells to create a Human Immune System mouse (HISmouse) model. We have found that these HISmice generate several subsets of B cells including B1 cells and the majority of them exhibit an immature B cell phenotype. Moreover, just as young children, HISmice responded poorly to PPS and sub-optimally to B. hermsii. Since IL-7 is produced mainly by non-hematopoietic stromal cells, and murine IL-7 is poor stimulator of human lymphocyte development, this impairment could be due to the lack of human IL-7-driven B cells in HISmice. In support of this we found that supplementation of HISmice with human IL-7 dramatically increases humoral responses to B. hermsii. The aims outlined in this proposal seek to: 1) determine whether IL-7 increases the number of polysaccharide- specific B1b cells; and 2) determine whether the B1b cells generated in the presence or absence of IL-7 are qualitatively different.